Laser imaging apparatus using biomedical markers that bind to cancer cells

ABSTRACT

A method for collecting data for use in image reconstruction of a tissue being scanned containing cancer cells comprises the steps of providing a source of laser beam; providing a biochemical marker that selectively binds to cancer cells within the tissue; directing the laser beam toward the object being scanned; orbiting the laser beam around the object; providing a plurality of sensors adapted to simultaneously detect the laser beam after passing through the object; and limiting the sensors to detect only the radiation released by the biochemical marker after having been activated by the laser beam.

FIELD OF THE INVENTION

[0001] This application is a related to provisional applications Ser.Nos. 60/036,088 and 60/063,590, filed on Jan. 17, 1997 and Oct. 30,1997, respectively, which are hereby incorporated by reference and whosepriorities are hereby claimed.

[0002] This application is also related to U.S. Pat. No. 5,692,511,issued to Richard J. Grable, which is hereby incorporated by reference.

FIELD OF THE INVENTION

[0003] The present invention relates generally to a diagnostic medicalimaging apparatus that employs a near-infrared laser as a radiationsource and more particularly to a method and apparatus for using abiochemical marker that selectively binds to cancer cells and emitsradiation when excited different from the apparatus laser beam toprovide a positive identification of the cancer site in a reconstructedimage of the scanned tissue.

BACKGROUND OF THE INVENTION

[0004] Cancer of the breast is a major cause of death among the Americanfemale population. Effective treatment of this disease is most readilyaccomplished following early detection of malignant tumors. Majorefforts are presently underway to provide mass screening of thepopulation for symptoms of breast tumors. Such screening efforts willrequire sophisticates, automated equipment to reliably accomplish thedetection process.

[0005] The x-ray absorption density resolution of present photographicx-ray methods is insufficient to provide reliable early detection ofmalignant tumors. Research has indicated that the probability ofmetastasis increases sharply for breast tumors over 1 cm in size. Tumorsof this size rarely produce sufficient contrast in a mammogram to bedetectable. To produce detectable contrast in photographic mammogram 2-3cm dimensions are required. Calcium deposits used for inferentialdetection of tumors in conventional mammography also appear to beassociated with tumors of large size. For these reasons, photographicmammography has been relatively ineffective in the detection of thiscondition.

[0006] Most mammographic apparatus in use today in clinics and hospitalsrequire breast compression techniques which are uncomfortable at bestand in many cases painful to the patient. In addition, x-rays constituteionizing radiation which injects a further risk factor into the use ofmammographic techniques as most universally employed.

[0007] Ultrasound has also been suggested as in U.S. Pat. No. 4,075,883,which requires that the breast be immersed in a fluid-filled scanningchamber U.S. Pat. No. 3,973,126 also requires that the breast beimmersed in a fluid-filled chamber for an x-ray scanning technique.

[0008] In recent times, the use of light and more specifically laserlight to non-invasively peer inside the body to reveal the interiorstructure has been investigated. This techniques is called opticalimaging. Optical imaging and spectroscopy are key components of opticaltomography. Rapid progress over the past decade have brought opticaltomography to the brink of clinical usefulness. Optical wavelengthphotons do not penetrate in vivo tissue in a straight line as do x-rayphotons. This phenomena causes the light photons to scatter inside thetissue before the photons emerge out of the scanned sample.

[0009] Because x-ray photons propagation is essentially straight-line,relatively straight forward techniques based on the Radon transform havebeen devised to produce computed tomography images through use ofcomputer algorithms. Multiple measurements are made through 360° aroundthe scanned object. These measurements, known as projections, are usedto back-project the data to create an image representative of theinterior of the scanned object.

[0010] In optical tomography, mathematical formulas and projectiontechniques have been devised to perform a reconstruction functionsomewhat similar to x-ray tomography. In order to perform an accuratereconstruction, the location of the points on the scanned object atwhich data are measured must be known.

[0011] In reviewing a reconstructed image of a tissue that has beenoptically scanned, there is a need to be able to identify the type ofobjects showing within the tissue. Once the object has been identifiedand its precise location determined, effective therapy is then initiatedbased on the photodynamic therapy drugs.

OBJECTS AND SUMMARY OF THE INVENTION

[0012] It is an object of the present invention to provide a laserimaging apparatus that uses a biochemical marker to provide a preciselocation of cancer cells within a tissue being scanned.

[0013] It is another object of the present to provide a laser imagingapparatus that uses a fluorophore that binds to cancer cells within atissue being scanned to provide a precise location of the cancer cellsby collecting the radiation intensity emitted by the fluorophore whenexcited by the laser beam of the apparatus.

[0014] It is still another object of the present invention to provide alaser imaging apparatus for imaging a lesion within a tissue and forproviding the appropriate wavelength for a laser to activate aphotodynamic therapy drug brought to the lesion by a biochemical marker.

[0015] It is another object of the present invention to provide a laserimaging apparatus for determining the shortest pathlength between thesurface of the tissue and the location of the lesion to allow efficientirradiation by laser energy of a photodynamic therapy drug attached tothe lesion.

[0016] It is also an object of the present invention to provide a laserimaging apparatus that can detect the presence and location of lesionwithin a tissue and at the same time providing therapy.

[0017] In summary, the present invention provides a method forreconstructing an image of a scanned object, comprising the steps ofproviding a source of laser beam; providing a biochemical marker thatselectively binds to cancer cells within the tissue; directing the laserbeam toward the object being scanned; orbiting the laser beam around theobject; providing a plurality of sensors adapted to simultaneouslydetect the laser beam after passing through the object; and limiting thesensors to detect only the radiation released by the biochemical markerafter having been activated by the laser beam.

[0018] The present invention also provides a method for activating aphotodynamic therapy (PDT) drug attached to abnormal cells within atissue, comprising the steps of providing a biochemical marker carryinga PDT drug within the tissue; scanning the tissue to locate the positionof the abnormal cells; determining the shortest path length for a laserbeam having a wavelength appropriate for the PDT drug; and directing thelaser beam toward the abnormal cells to activate the PDT drug.

[0019] The present invention also provides an apparatus for imaging anobject, comprising a scanning chamber for receiving therein an objectbeing scanned; a source of laser beam disposed within the scanningchamber for impinging on the object being scanned, the laser beam beingadapted to orbit around the object; an array of sensors disposed withinthe chamber, each of the sensors being adapted to detect radiationemanating from a biochemical marker attached to cancer cells; and acomputer programmed to take the output of each detector at everylocation in the orbit around the object to reconstruct an image of theobject.

[0020] These and other objects of the present invention will becomeapparent from the following detailed description.

BRIEF DESCRIPTIONS OF THE DRAWINGS

[0021]FIG. 1 is a schematic side elevational view of a scanningapparatus including a scanning chamber made in accordance with thepresent invention, showing a patient positioned on a support platformwith her breast pendent within the scanning chamber for opticaltomographic study.

[0022]FIG. 2 is a schematic plan view of the scanning chamber of FIG. 1,showing the restricted field of views of the respective detectors andthe optical chord lengths of the laser beam through the object.

[0023]FIG. 3 is a schematic block diagram of a circuit for collectingdata from each detector.

[0024]FIG. 4 is a schematic diagram of the scanning chamber of FIG. 2.

[0025]FIG. 5 is a response curve representing the data points for eachof the detectors at each angular position in the orbit of the scanner.

[0026]FIG. 6 is an enlarged cross-sectional view of a detector assemblyshowing an optical filter disposed in front of a photodetector.

[0027]FIG. 7A shows a biochemical tag binding with a malignant cell.

[0028]FIG. 7B is a schematic view of a colony of cancer cells to which abiochemical marker have bonded and shows the biochemical tag emittingradiation after having been excited by the laser.

[0029]FIG. 8 shows the excitation and emission spectra of a fluorophoreas seen by a detector.

[0030]FIG. 9 is similar to FIG. 8, with the emission spectrum modifiedby a cut-off filter.

[0031]FIG. 10 is similar to FIG. 8, with the emission spectrum modifiedby a bandpass filter.

[0032]FIG. 11A shows a biochemical tag with an accompanying photodynamictherapy drug binding with a malignant cell.

[0033]FIG. 11B is a schematic view of a colony of cancer cells to whicha biochemical marker carrying a photodynamic therapy drug have bondedand shows activating laser beam impinging on the drug.

[0034]FIG. 12 is a schematic plan view of the scanning chamber of FIG.1, showing the positioning of the laser beam to provide the minimum pathlength to a cancer site bearing photodynamic therapy drug transported bya biochemical marker.

DETAILED DESCRIPTION OF THE INVENTION

[0035] A scanning apparatus 2, such as that described in U.S. Pat. No.5,692,511 is schematically disclosed in FIG. 1. A patient 4 ispositioned prone on a top surface of the apparatus 2 with her breast 6pendent within a scanning chamber 8. A laser beam from a laser source 10is operably associated with the scanning chamber 8 to illuminate thebreast 6.

[0036] The scanning chamber 8 is shown schematically in plan view inFIG. 2. The scanning chamber includes a plurality of detector assemblies12 disposed in an arc to define an opening in which an object 14 to bescanned, such as the breast, is positioned. A laser beam 16 impinges theobject at point 18. Light exiting from the object 18, such as the rays20 is picked up by the respective detector assembly 12, which is thenused to provide an image of the scanned object. The rays 20 arerepresented as chords originating from the point of entry 18 of thelaser beam 16 and exiting at various points on the perimeter of thescanned object. The detector assemblies 12 are digitally orbited aroundthe object 14 about an orbit center 22 at equal angular increments for atotal angular displacement of 360°. The object is illuminated with thelaser beam 16 at each angular position in the orbit 23 and lightemerging from the object depicted by the chords 20 on the perimeter ofthe scanned object, at one instant in time or in a period of timeacquired simultaneously, is picked up by the respective detectorassemblies 12. Each detector assembly has its longitudinal axis directedtoward the orbit center 22. The detector assemblies 12 are secured to asupport 36, which is orbited in orbit 23 around the object 14 beingscanned. After each complete orbit, the array of detector assemblies 12and the laser beam 16 are moved vertically to a new position to scan adifferent slice plane of the object. This is repeated until all theslice planes of the object has been scanned.

[0037] Each detector assembly 12 includes an opaque housing 24 with anopen front end 26 and a rear end 28 in which a detector 30 is disposed.A fiber-optic cable (not shown) may be used to connect the rear end 28of the tube to a remotely located detector 30 to advantageously spaceout the detectors from each other to minimize noise signals. The insidesurface of the housing 24 can be tubular, round, square or othercross-sectional shape. The housing 24 is designed to restrict the fieldof view of its respective detector 30, such that each detector is onlylooking at its own small area of the scanned object. The field of viewof each detector assembly 12 is schematically indicated at 32. A patchor surface seen on the scanned object by the respective detectorassembly is schematically indicated at 34.

[0038] The field of view 32 and the respective patch of surface 34 areconfigured such that adjacent patches of surface do not overlap eachother. In this way, each detector assembly is uniquely assigned to apatch of surface at each angular position of the orbit so that lightcoming from one patch of surface could only be detected by therespective detector whose field of view covers that particular patch ofsurface. Each detector 30 is active to detect any light emerging fromits respective patch of surface, since the light beam 16 can coursethrough the object in any paths, such as those depicted by the chords20. Each housing 24 is further described in a copending application Ser.No. 08/963,760, filed Nov. 4, 1997, which is hereby incorporated byreference.

[0039] Each detector or sensor 30 is operably connected to itsrespective sample and hold integrator 40, as best shown in FIG. 3. Amultiplexer 42 is used to connect the respective integrator outputs toan analog-to-digital converter 44. The digitized individual detector orsensor response is stored in memory 46 for later use in imagereconstruction by a computer 47. The circuit allows for simultaneousacquisition of data from all the detectors 30 at each angular positionin the orbit of the scanning chamber 8. The sample and hold integrator40 is further described in a copending application Ser. No. 08/979,328,filed on Nov. 26, 1997, which is hereby incorporated by reference.

[0040] Perimeter data of the object being scanned is obtained at eachangular position in the orbit of the scanning chamber 8. Several methodsare disclosed in copending applications Ser. Nos. 08/965,148 and08/965,149 filed on Nov. 6, 1997, which are hereby incorporated byreference. One method is to use a sensor array 49 disposed on the sameside as the laser beam 16, as best shown in FIG. 2. The laser beam 16impinges on the scanned object through the center of the orbit. Brightspot is produced at point 18. At each distance from the orbit center, aspecific element in the sensor array 49 will detect the bright spot. Asthe laser beam 16 and the rest of the scanner are orbited around thescanned object about the center, the output signal of the sensor array49 will be in direct relationship to the perimeter of the scannedobject. By acquiring data using one or more known diameters scannedobjects, the level of the sensor signal can be calibrated with respectto the scanned object diameters. After calibration, the sensor signalcan be electronically decoded to plot the coordinates for the perimeterof the scanned object as the scanner is orbited around the scannedobject.

[0041] It is advantageous to obtain the perimeter data during datacollection of each slice to minimize error due to shifting of the objectbetween slice positions. Perimeter data and the corresponding detectordata are used together to reconstruct the image of the object. Perimeterdata consist of distances from the center of orbit at each angularposition of the orbit.

[0042] The scanning chamber 8 is represented schematically in FIG. 4.The detectors 30 are shown as AA, BB, . . . , KK, indicating theirrespective positions along the arc. Optical path lengths taken by thelaser beam through the object are represented as chords 18-A, 18B, . . ., 18-K. At each angular position in the orbit 23, the data collected bythe detectors AA, BB, . . . , KK are generally indicated by the responsecurve 48 shown in FIG. 5. The signals seen by the detectors AA and KKare strongest because of the shorter chord lengths 18-A and 18-K. Thesignal seen by the detector FF is smaller because of its correspondinglonger chord length 18-F. It is therefore seen that the signal generallydecreases from detectors AA to FF and increases from detectors FF to KK.

[0043] The data represented by the curve 48 and the perimeter data ateach angular position of orbit are collected simultaneously, until theorbit has traversed a complete circle. Data taken during each orbit ofthe scanner 8 is used to reconstruct an image of the scanned objectusing computerized tomographic techniques. Copending application Ser.No. 08/979,624, filed on Nov. 28, 1997, discloses a method for imagereconstruction, which is hereby incorporated by reference.

[0044] Each detector assembly 12 is provided with an optical filter 50to limit the spectral response of the detector 30 within the restrictedfield of view. The filter 50 may be a bandpass filter or cut-off filter.The purpose of the filter 50 will become apparent from the followingdisclosure.

[0045] A biochemical marker or tag is advantageously used to provide ahigh signal-to-noise ratio in the response curve 48 and provide preciselocation of the malignant cells within the breast. The biochemical tag51 binds with malignant cells 52 within a colony of normal cells 54, asbest shown in FIG. 7A. The biochemical tag 50 has a fluorescentcharacteristic radiation 55 when illuminated by a beam of monochromaticlight 16, as best shown in FIG. 7B. The wavelength of the fluorescentradiation is far enough from the excitation beam wavelength, on theorder of 5-35 nm, to allow detection of the fluorescent radiation by thedetector 30. The excitation beam 16 is represented by the curve 56 andthe fluorescent radiation by the curve 58, as best shown in FIG. 8. Theoptical filter 50 is provided to further enhance the ability of thedetector 30 to respond only to those wavelengths that correspond to theemission spectrum 58 of the fluorescent compound.

[0046] Referring to FIG. 9, the filter 50 comprises an optical cut-offfilter. The emission spectrum 58 of the fluorescent compound orfluorophore has been modified by the cut-off filter, represented by thearea 60, to limit the spectrum range seen by the detector 30. Thecut-off filter significantly attenuates wavelengths shorter than thecut-off limit and further isolates the detector 30 from the excitationspectrum 56 while allowing the emission wavelengths to pass through thefilter and reach the detector 30.

[0047] Referring to FIG. 10, the filter 50 comprises a band-pass filterto limit the spectral range seen by the detector 30. The band-passfilter modifies the emission spectrum 58 by cutting off wavelengthsshorter and longer than the band-pass limits, as illustrated by areas 62in FIG. 10.

[0048] When the fluorescent compound is introduced into the body, itwill bind to malignant cells. In breast imaging, introduction of thefluorescent compound into the body will result in specific tagging ofmalignant cells in the breast. When the breast is irradiated with anintense beam of light at the proper wavelength, the fluorescent compoundwill emit light at its natural frequency. The detectors 30 in thescanner fitted with optical cut-off or band-pass filters allow only thefluorescent spectrum to stimulate the detector. The opticalreconstruction algorithm will display the position of the fluorescencewithin the boundaries of the scanned breast. Because only thefluorescent compound emits a narrow spectrum of light and the detectorsare fitted with appropriate filters to see only this spectrum, a highsignal-to-noise ratio is advantageously obtained and precise location ofthe malignant cells within the breast is possible.

[0049] Collagen is a fluorophore with an absorption (excitation) bandwavelength of 488 nm and an autofluorescence wavelength of 500+ nm.Peridinin-Chlororophyll, disclosed in U.S. Pat. No. 4,876,190, isanother biochemical marker with an absorption (excitation) bandwavelength of 440 nm and autofluorescence wavelength of 660 nm.

[0050] Certain drugs, called photodynamic therapy (PDT) drugs can beactivated by selected wavelengths of light. It is desirable to limit thearea of activation of the PDT drug only to cancer locations. The abilityto image the breast to establish location in the breast of suspect areasand the ability to locate fluorescence within the breast provide thebasis for therapy planning for PDT. Referring to FIG. 11A, a biochemicaltag 51 with an accompanying photodynamic therapy drug 64 is seen to bindwith malignant cells 52 within a colony of normal cells 54. Theselective nature of the biochemical marker 51 ensures the delivery ofthe photodynamic therapy drug 62 to the cancer cells 52. The lasersource 16 is tuned to provide a specific wavelength for the activationof the PDT drug, as best shown in FIG. 11B. Such a tunable laser iswell-known in the art. By knowing the location of the fluorescence, andthus the location of the cancer, determination of the least path foraiming the laser beam 16 to the cancer site is therefore provided foreffective therapy.

[0051] Lutetium Texaphyrin PCI-0123 (Lu-Tex) is an example of a PDTdrug. It has an absorption band wavelength of 732 nm, 90% lightabsorption in the 723-741 nm wavelength range. It is available fromPharmacyclics, Inc. Photofrin is another example. It has an absorptionwavelength of 632 nm, and available from QTL Photo Therapeutics, Inc.,Toronto, Canada. Yet another example is long-wavelength water solublechlorine photosensitizers useful for photodynamic therapy and diagnosisof tumors, disclosed in U.S. Pat. No. 5,330,741, with an absorptionwavelength of 600-800 nm.

[0052] Referring to FIG. 12, the breast 6 with a cancer site 66 has beenscanned by scanner 8, providing an exact location of the cancer cellsdue to the fluorescence of the biochemical marker which had attached tothe cancer cells. The optical filters 50 are represented schematicallyat 68. The scanner is then repositioned to provide the shortest pathlength for the laser beam 16 to the cancer site 64. The wavelength ofthe laser beam 16 is selected to activate the PDT drug.

[0053] While breast cancer detection is the primary focus of the presentinvention, a person of ordinary skill in the art will understand that itcould also be applied to other parts of the body.

[0054] While this invention has been described as having a preferreddesign, it is understood that it is capable of further modification,uses and/or adaptations following in general the principle of theinvention and including such departures from the present disclosure ascome within known or customary practice in the art to which theinvention pertains, and as may be applied to the essential features setforth, and fall within the scope of the invention or the limits of theappended claims.

We claim:
 1. A method for collecting data for use in imagereconstruction of a tissue being scanned containing cancer cells,comprising the steps of: a) providing a source of laser beam; b)providing a biochemical marker that selectively binds to cancer cellswithin the tissue; c) directing the laser beam toward the object beingscanned; d) orbiting the laser beam around the object; e) providing aplurality of sensors adapted to simultaneously detect radiation exitingfrom the object; and f) limiting the sensors to detect only theradiation released by the biochemical marker after having been activatedby the laser beam.
 2. A method as in claim 1, wherein said limiting isimplemented with an optical bandpass filter operably associated witheach detector.
 3. A method as in claim 1, wherein said limiting isimplemented with an optical cut-off filter operably associated with eachdetector.
 4. A method as in claim 1, wherein the biochemical marker is afluorophore.
 5. A method for activating a photodynamic therapy (PDT)drug attached to abnormal cells within a tissue, comprising the stepsof: a) providing a biochemical marker carrying a PDT drug within thetissue; b) scanning the tissue to locate the position of the abnormalcells; c) determining the shortest path length for a laser beam having awavelength appropriate for the PDT drug; and d) directing the laser beamtoward the abnormal cells to activate the PDT drug.
 6. A method as inclaim 5, wherein said scanning is implemented with detectors adapted toreceive only radiation emitted by the biochemical marker.
 7. A detectorarray for a laser imaging apparatus, comprising: a) a plurality ofdetectors disposed in an arc around an opening in which a tissue to bescanned is disposed; and b) each of said detectors including an opticalwavelength restricting filter matched to the wavelength of radiationemitted by a biochemical marker within the tissue after being activatedby a laser beam.
 8. A detector array as in claim 7, wherein said filteris a bandpass filter.
 9. A detector array as in claim 7, wherein saidfilter is a cut-off filter.
 10. An apparatus for imaging an object,comprising: a) a scanning chamber for receiving therein an object beingscanned; b) a source of laser beam disposed within said scanning chamberfor impinging on the object being scanned, said laser beam being adaptedto orbit around the object; c) an array of sensors disposed within saidchamber, each of said sensors being adapted to detect radiationemanating from a biochemical marker attached to cancer cells; and d) acomputer programmed to take the output value of each detector at everylocation in the orbit around the object to reconstruct an image of theobject.
 11. An apparatus as in claim 10, wherein each of said sensorsinclude a bandpass filter.
 12. An apparatus as in claim 10, wherein eachof said sensors includes a cut-off filter.